Obesity results from an imbalance between energy intake and energy expenditure and often is associated with respiratory disorders including obstructive sleep apnea, hypoventilation, and hypoxemia. The consequences of obesity-related respiratory disease range from excessive daytime sleepiness to severe cardiopulmonary disorders. The mechanisms that are responsible for obesity-associated disorders remain to be clarified; however, it is likely that changes in neural input to regions of the brain that control the activity of upper airway dilating and chest wall pumping muscles are involved. Our preliminary data provide evidence that leptin, a neurohumoral substance with anorexigenic properties, modulates respiratory drive via an area in the brain that is above the brain stem. Thus, we hypothesize that leptin activates neurons in the hypothalamus that project to a common respiratory-related network within the medulla oblongata to alter respiratory patterns and/or responses to hypercapnia. In Specific Aim 1, we will identify the neurochemical content of hypothalamic neurons that are activated by leptin and project to a respiratory rhythm-generating region in the medulla by combining neuroanatomical and physiological techniques. The goal of Specific Aim 2 is to determine the effects of stimulation of hypothalamic cells that are activated by leptin on inspiratory-related neuronal activity in the respiratory-related network and on phrenic and hypoglossal nerves that control the activity of upper airway dilating and chest wall pumping muscles. In Specific Aim 3, we will use neurochemical, molecular, pharmacologic, and physiologic techniques to test our hypothesis that leptin affects respiratory activity and alters ventilatory responses to changes in chemical drive via hypothalamic neurons that are activated by leptin and project to the respiratory rhythm-generating region in the medulla. This information may serve as a basis for designing new evidence-based therapeutic strategies that can reduce or alleviate severe cardiopulmonary consequences of respiratory disorders.